More than three billion people, one-half of humanity, are infected with parasitic nematodes. These pathogens are the main causative agents of neglected diseases, causing mortality and morbidity in humans and interfering with normal development in children. Parasitic nematodes reduce productivity of food animals and crops which are critical for economical and nutritional well-being, especially for people in developing countries. The biological and genomic complexity of nematodes has impeded the clarification of principles that could have general application towards advancing parasite control. Our research is intended to resolve this complexity substantially by partitioning it into conserved and diverse genetic elements that have been retained or have evolved throughout the evolution of the Nematoda. Our focus is on the nematode intestine, which is a metabolically active interface with the host and its immune system. While it is a demonstrated target for both immune- and chemo-therapeutic approaches to parasite control, very little is known regarding the conserved and variable features of this interface. Uncovering the evolutionary principles underlying both conserved and adaptable features of the nematode intestine will provide the research community with optimal targets for effective parasite control. The three aims in this proposal focus on providing a comprehensive understanding of genes that are expressed in the adult nematode intestine from parasites that span the evolutionary extremes of the phylum. The intestinal transcriptomes from the selected core species will be used to determine the pan-Nematoda intestinal transcriptome. Advanced bioinformatic approaches will be applied to delineate intestinal genes from all other available nematode genomes, emphasizing human pathogens that are too small to support direct analysis of intestinal functions. Intestinal protein families will be investigated to identify those that have undergone births or deaths and expansions or contractions throughout nematode evolution. Finally, we will determine functional categories of intestinal protein families that reflect adaptable traits of the highest importance in evolution of parasitism. Resulting knowledge is essential to understand molecular features of nematode intestinal cells that facilitate nutrient acquisition in diverse trophic environments, while coping with hazards that accompany exposure at this key interface with the host. In turn, that knowledge will guide strategies to circumvent critical parasite functions by immunological or chemotherapeutic means. PUBLIC HEALTH RELEVANCE: Parasitic nematodes are a major cause of neglected diseases in over half of the world's population, and are a leading cause of human morbidity. The main goal of this project is through implementation of comparative genomics and experimental approaches to advance principles that will have broad application to immune control of parasitic nematodes. This will be accomplished by identifying molecular and cellular features of the nematode intestine that are conserved across the Nematoda or have figured decisively in the adaptive evolution of nematode pathogens. The nematode intestine is demonstrated to be the critical interface with the host; therefore, it is the most versatile tissue for control or prevention. The gained knowledge will focus research on cellular targets with the broadest application to parasite control.